Abstract
Poly(ADP-ribose) polymerase (PARP)10 is a PARP family member that performs mono-ADP-ribosylation of target proteins. Recent studies have linked PARP10 to metabolic processes and metabolic regulators that prompted us to assess whether PARP10 influences mitochondrial oxidative metabolism. The depletion of PARP10 by specific shRNAs increased mitochondrial oxidative capacity in cellular models of breast, cervical, colorectal and exocrine pancreas cancer. Upon silencing of PARP10, mitochondrial superoxide production decreased in line with increased expression of antioxidant genes pointing out lower oxidative stress upon PARP10 silencing. Improved mitochondrial oxidative capacity coincided with increased AMPK activation. The silencing of PARP10 in MCF7 and CaCo2 cells decreased the proliferation rate that correlated with increased expression of anti-Warburg enzymes (Foxo1, PGC-1α, IDH2 and fumarase). By analyzing an online database we showed that lower PARP10 expression increases survival in gastric cancer. Furthermore, PARP10 expression decreased upon fasting, a condition that is characterized by increases in mitochondrial biogenesis. Finally, lower PARP10 expression is associated with increased fatty acid oxidation.
Highlights
Poly(ADP-ribosyl)ation (PARylation) is an evolutionarily conserved biochemical reaction that involves the catalytic cleavage of NAD+ to nicotinamide and ADP-ribose and the subsequent addition of the ADP-ribose (ADPR) moiet(ies) to acceptor proteins [1]
Mitochondrial fatty acid oxidation was blocked by 50 μM of etomoxir, which inhibits carnitin palmitoyltransferase and substrate preference was judged as change in oxygen consumption rate (OCR)
Fatty acid oxidation was enhanced in all cell lines upon PARP10 silencing, it was statistically significant only in Hela and Capan2 cells (Fig 1B, fatty acid oxidation (FAO) = baseline—Glc+AA)
Summary
Poly(ADP-ribosyl)ation (PARylation) is an evolutionarily conserved biochemical reaction that involves the catalytic cleavage of NAD+ to nicotinamide and ADP-ribose and the subsequent addition of the ADP-ribose (ADPR) moiet(ies) to acceptor proteins [1]. Poly(ADP-ribose) polymerase (PARPs/ARTDs) are the enzymes responsible for cellular PARylation. “Classical” PARP enzymes (e.g. PARP1, PARP2) cleave NAD+, transfer ADPR to target proteins in an iterative process that results in the synthesis of protein-bound ADPR polymers (PAR). Not all PARPs are capable of PARylation.
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